Oral TP-3654 for Myelofibrosis

Recruiting at 58 trial locations

Overseen By Jordan Simpson

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Sumitomo Dainippon Pharma Oncology, Inc

Must be taking: Ruxolitinib, Momelotinib

Must not be taking: Systemic steroids

Disqualifiers: Chronic liver disease, Heart failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 12

Duration: 24 weeks

240 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is a Phase 1/2, multicenter, dose-escalation, open-label trial to assess safety, tolerability, pharmacokinetics and pharmacodynamics of nuvisertib (TP-3654) in patients with intermediate or high-risk primary or secondary MF.

Do I need to stop my current medications to join the trial?

The trial does not specify that you must stop all current medications, but certain treatments like systemic antineoplastic therapy or experimental therapies must be stopped at least 2 weeks or 5 half-lives before starting the trial. If you are on a JAK inhibitor like ruxolitinib, you may need to taper off over at least 1 week. Hydroxyurea or anagrelide can be taken up to 24 hours before starting the trial.

What makes the drug TP-3654 unique for treating myelofibrosis?

TP-3654, also known as Nuvisertib, is unique because it is an oral treatment for myelofibrosis, which may offer a different mechanism of action compared to existing JAK2 inhibitors like fedratinib and ruxolitinib. While the specific details of TP-3654's action in myelofibrosis are not provided, its development suggests it may target pathways not addressed by current standard treatments. ^{1 2 3 4 5}

Eligibility Criteria

This trial is for adults with primary or secondary myelofibrosis, a type of bone marrow cancer. They must have tried and failed JAK inhibitor treatment or be ineligible for it. Participants need to have certain blood counts, organ function within specific limits, and a life expectancy of at least 3 months. They can't join if they've had recent surgeries or other treatments that could interfere with the study.

Inclusion Criteria

I agree to give bone marrow samples at the start and every 6 months during the study.

My spleen is enlarged, confirmed by a doctor's exam or imaging tests.

- Life expectancy ≥ 3 months

Exclusion Criteria

My electrolyte levels are stable or can be corrected.

I haven't had cancer treatment or experimental therapy in the last 14 days or 5 half-lives, whichever is longer.

I have had my spleen removed or received spleen radiation in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nuvisertib (TP-3654) in various combinations depending on the arm, with dose-escalation to assess safety, tolerability, pharmacokinetics, and pharmacodynamics

24 weeks

Regular visits for dose-escalation and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of spleen volume reduction and symptom score improvement

12 weeks

Every 12 weeks from cycle 1 day 1 through cycle 19 day 1, and then every 24 weeks thereafter during treatment

Long-term follow-up

Participants are monitored for overall survival and long-term safety outcomes

From start of treatment to end of study

Treatment Details

Interventions

• TP-3654

Trial Overview The trial is testing TP-3654, an oral medication for myelofibrosis patients who are at intermediate or high risk. It's in early stages (Phase 1/2) to see how safe it is and how the body responds to different doses. Patients will also undergo regular bone marrow biopsies to monitor effects.

Participant Groups

Group I: Arm 3: nuvisertib (TP-3654) in combination with momelotinib Experimental Treatment 2 Interventions

Group II: Arm 2: nuvisertib (TP-3654) added on to ruxolitinib Experimental Treatment 2 Interventions

Group III: Arm 1: nuvisertib (TP-3654) Experimental Treatment 1 Intervention

Who Is Running the Clinical Trial?

Sumitomo Dainippon Pharma Oncology, Inc

Lead Sponsor

Trials

42

Recruited

6,800+

Sumitomo Pharma Oncology, Inc.

Lead Sponsor

Trials

45

Recruited

7,100+

Sumitomo Pharma America, Inc.

Lead Sponsor

Trials

244

Recruited

51,500+

Jatin Shah

Sumitomo Pharma America, Inc.

Chief Medical Officer since 2024

MD from an unspecified institution

Tsutomu Nakagawa

Sumitomo Pharma America, Inc.

Chief Executive Officer since 2024

MBA from Waseda University

Findings from Research

Ruxolitinib is an effective oral treatment for intermediate- or high-risk myelofibrosis, targeting JAK1 and JAK2 to reduce spleen size and improve symptoms, as demonstrated in Phase III trials with significant improvements in quality of life and overall survival.

The treatment has a manageable safety profile, with common side effects including anemia and thrombocytopenia, and requires dosage adjustments based on platelet counts, allowing for personalized patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of primary myelofibrosis. Swaim, SJ.[2021]

Fedratinib, an oral JAK2 inhibitor, is effective and safe for treating myelofibrosis in patients with low platelet counts (50 to <100 × 10^9 /l), showing similar spleen and symptom response rates compared to patients with higher platelet counts in two clinical trials involving 193 patients.

While new or worsening thrombocytopaenia occurred more frequently in patients with low platelet counts (44% vs. 9% in high platelet counts), it was manageable with dose adjustments, and no serious thrombocytopaenia events were reported, indicating that initial dose adjustments for fedratinib are not necessary for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of fedratinib, a selective oral inhibitor of Janus kinase-2 (JAK2), in patients with myelofibrosis and low pretreatment platelet counts. Harrison, CN., Schaap, N., Vannucchi, AM., et al.[2022]

In a study of 290 patients with myelofibrosis who discontinued ruxolitinib, half developed cytopenias, indicating a significant increase in morbidity after stopping the treatment.

The median overall survival after discontinuation was 11.1 months, with age, comorbidity index, and gender identified as key risk factors affecting treatment progression and survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient characteristics and outcomes after ruxolitinib discontinuation in patients with myelofibrosis. Mascarenhas, J., Mehra, M., He, J., et al.[2021]

In a pivotal phase III trial, fedratinib, an oral JAK2 inhibitor, demonstrated significant efficacy in treating myelofibrosis, with a 47% spleen volume response rate and a 40% symptom response rate at 24 weeks, compared to only 1% and 9% for placebo.

Fedratinib was generally well-tolerated, with common side effects including diarrhea, nausea, anemia, and vomiting, but notably, there were no cases of Wernicke encephalopathy reported in patients taking the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis. Pardanani, A., Tefferi, A., Masszi, T., et al.[2022]

Pacritinib has shown promising efficacy in treating myelofibrosis (MF), with 31% of patients experiencing a significant reduction in spleen volume and 42% showing improvement in spleen size through physical examination after 24 weeks.

The treatment demonstrated a favorable safety profile, particularly for patients with preexisting anemia and thrombocytopenia, although common side effects included diarrhea and nausea, leading to treatment discontinuation in 26% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis. Komrokji, RS., Seymour, JF., Roberts, AW., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of primary myelofibrosis. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of fedratinib, a selective oral inhibitor of Janus kinase-2 (JAK2), in patients with myelofibrosis and low pretreatment platelet counts. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Patient characteristics and outcomes after ruxolitinib discontinuation in patients with myelofibrosis. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Updated results of the placebo-controlled, phase III JAKARTA trial of fedratinib in patients with intermediate-2 or high-risk myelofibrosis. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis. [2022]